Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.

A "Four Core Genotypes" rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases.

Background: We have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype. Methods: XY rats were produced with an autosomal transgene of Sry , the testis-determining factor gene, which were fathers of XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females that have XX and XY progeny with ovaries. These groups can be compared to detect sex differences caused by sex chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Results: We have measured numerous phenotypes to characterize this model, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Numerous phenotypes previously found to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development. Conclusion: The results establish a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.

Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation.

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the four core genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect, and last, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions.

The Impact of Alternative Foods on Consumers' Continuance Intention from an Innovation Perspective.

This paper aims to model consumers' perceptions and preferences toward alternative foods. We conducted a survey of 519 people and analyzed their responses using a structural equation model. The article discusses the role of food innovation quality (FIQ), a concept developed from innovative design, which shows how consumers perceive the quality of products in an innovative context. Further, the paper discusses the relationship between this concept and promoting consumer acceptance of alternative foods. Studies suggest that higher FIQ may lead to increased consumer satisfaction with alternative foods, which may in turn lead to higher levels of trust and continuation. Moreover, expectations play a significant role in FIQ and in the perceived value of alternative foods in the model. This illustrates that the promotion of alternative foods in an innovative manner should include establishing a practical mechanism for meeting consumer expectations. Given the continued growth in global food demand, it is both effective and beneficial to promote alternative foods through innovative design as part of a broader food industry approach. On the one hand, alternative foods produced in an innovative manner serve to energize the consumer market by expanding dietary choices. On the other hand, alternative foods, which include new forms of meat products, contribute to the alleviation of the problem of meat production capacity in agriculture. In addition, the alternative foods process eliminates the emission of large amounts of carbon dioxide by traditional agriculture, increasing the sustainability of food production.

COVID-19 risk perception and restaurant utilization after easing in-person restrictions.

This article investigated the influence of risk aversion and the perception of risk associated with dining inside a restaurant on restaurant utilization and expenditures in the initial re-opening phase of the COVID-19 pandemic. Consistent with economic theory, risk aversion and perception decreased the use of in-person restaurant services and increased the probability of using take-out and delivery, but had no influence on total restaurant expenditures. Risk perception had a larger effect on indoor dining compared to outdoor dining, suggesting risk averting behavior within the utilization of in-person restaurant services. These findings suggest COVID-19 concerns may influence restaurant use even after states relax their policies restricting restaurant operations. Our results also highlight the importance of developing policies to support the restaurant industry as consumers adjust to the re-opening phase of the pandemic.

Agent-based Modeling to Evaluate Human-Environment Interactions in Community Flood Risk Mitigation.

This article deals with household-level flood risk mitigation. We present an agent-based modeling framework to simulate the mechanism of natural hazard and human interactions, to allow evaluation of community flood risk, and to predict various adaptation outcomes. The framework considers each household as an autonomous, yet socially connected, agent. A Beta-Bernoulli Bayesian learning model is first applied to measure changes of agents' risk perceptions in response to stochastic storm surges. Then the risk appraisal behaviors of agents, as a function of willingness-to-pay for flood insurance, are measured. Using Miami-Dade County, Florida as a case study, we simulated four scenarios to evaluate the outcomes of alternative adaptation strategies. Results show that community damage decreases significantly after a few years when agents become cognizant of flood risks. Compared to insurance policies with pre-Flood Insurance Rate Maps subsidies, risk-based insurance policies are more effective in promoting community resilience, but it will decrease motivations to purchase flood insurance, especially for households outside of high-risk areas. We evaluated vital model parameters using a local sensitivity analysis. Simulation results demonstrate the importance of an integrated adaptation strategy in community flood risk management.

Understanding the Key Factors of Older Adults' Continuance Intention in Congregate Meal Halls.

Eating congregate/community meals with friends promotes a balanced and healthy diet among older adults. It is helpful for postponing aging, preventing chronic diseases, and improving their quality of life. However, little research has examined the continuance intention for older adults with the congregate meal program in Taiwan. This study established a model for key factors of older adults' continuance intention dining at senior meal halls, and hypotheses to explain them, and subsequently designed questionnaires and scales. By analyzing the longitudinal data collected from 416 individuals using survey questionnaires, we found that the perceived service quality is the main factor that affects the perceived satisfaction, and the perceived satisfaction of the older adults plays an important role in this survey. It showed that if the older adults are satisfied with the service quality provided by the senior meal halls, which will accordingly affect the post-use trust, they will show a positive continuance intention to participate in the senior meal halls. We also found that the older adults have positive views on the planning and service contents of the existing senior meal halls. Together, these results illustrate the process and provide comprehensive insights and evidence to create a better user experience and improve the satisfaction of the congregate meal for older adults.

Vibrational Fingerprint Analysis of an Azo-based Resonance Raman Scattering Probe for Imaging Proton Distribution in Cellular Lysosomes.

Due to the fundamental mechanism of vibrational state transitions for chemical bonds, the spectra of Raman scattering are narrow-banded and photostable signals capable of probing specific reactions. In the case of protonation/deprotonation reactions, certain chemical bonds are broken and new bonds are formed. Based on the changes of the vibrational modes for the corresponding bonds, fingerprint analysis of multiple Raman bands may allow for the in situ visualization of proton distribution in live cells. However, Raman scattering faces the well-known challenge of low sensitivity. To perform the vibrational fingerprint analysis of Raman scattering by overcoming this challenge, we developed an azo-based resonance Raman pH probe. It was an azobenzene-featured small molecule responsive to protons with the inherent Raman signal ∼104-fold more intense than that of the conventional alkyne-type Raman reporter 5-ethynyl-2'-deoxyuridine. Through the substitution of the electron-donating and -withdrawing entities to the azobenzene group, the effect of resonance Raman scattering and fluorescence quenching was obtained. This effect resulted in a significant Raman enhancement factor of ∼103 compared to the counterpart molecules without the molecular design. Based on the enhanced Raman sensitivity of the azo-based resonance Raman pH probe, the identification of vibrational fingerprint changes at the azo group was achieved during the protonation/deprotonation reactions, and the vibrational fingerprint analysis resolved a pH difference of less than 0.2 unit. The method enabled sensitive hyperspectral cell imaging that clearly visualized the change of proton distribution in autophagic cells.

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states.

A new analytical platform for potential point-of-care testing of circulating tumor cells.

It is of significance to detect circulating tumor cells (CTCs) in whole blood using transportable instruments at the point of care to assist evaluating chemotherapeutic efficacy and recurrence risk of cancer patients. However, the current widely used detection methods either require expensive and complex equipments, need complicated enrichment steps, or produce high rates of false positive and/or negative results. Aiming for solving the two critical challenges involved in instrumentation miniaturization and simplification of sample preparation for POCT of CTCs without sacrificing the detection sensitivity and accuracy, this work reports a custom-built, automatic, large field-of-view microscopic CTC cytometer and a novel enrichment strategy based on a synthesized peptide ligand discovered from One-Bead One-Compound library screening. The custom-built microscope has compact size, low weight and efficient cost while still maintaining a detection limit of as low as 5 target objects. The simplified sample preparation utilized a novel peptide LXW7 functionalized to magnetic beads and allows for rapid, highly selective and sensitive detection of CTCs. This analytical platform may fulfill the unmet need for possible point-of-care CTC counting, and provide a new option for early diagnosis of cancers and convenient evaluation of chemotherapeutic efficacy and cancer recurrence.

Consumer Food Waste Behavior among Emerging Adults: Evidence from China.

With the aggravation of global climate change, the issue of environmental protection has become the focus of global attention, and countries all over the world have devoted themselves to the sustainable development of resources to reduce the negative impact of the environment on human society. Reducing the resource waste is an important aspect of the sustainable development, among which food waste is a critical part. According to a report of the United Food and Agriculture Organization of the United Nations (FAO), 35% of food is wasted during consumption. Although households are the main contributors to food waste during consumption, the situation in university canteens cannot be ignored. As universities have a high degree of social influence, some policies and activities are piloted in universities, and then, promoted to society after achieving significant results. In future social development, the food waste behavior of consumers at the early stage of adulthood will have a significant impact on society. Therefore, it is necessary to understand the factors that lead to food waste by early adulthood consumers. This study focuses on food waste by end consumers and explores factors in the food waste behavior of the emerging adulthood consumer, which can be used as a reference for improving food waste in schools, governments, and other related industries in the future. The results show that the model of factors influencing the food waste behavior of emerging adulthood consumers established in this study is acceptable. According to the analysis results of the structural equation modeling (SEM), it can be seen that the influences of environmental concerns on the attitude toward behavior, subjective norms, and perceived behavioral control are ranked first, second, and third, respectively. While emerging adulthood consumers have a high degree of independence and self-awareness, schools, governments, media networks, and other related industries also need to establish a more complete system and form of cherishing food, in order to encourage emerging adulthood consumers to change their behavior and attitude spontaneously.

X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity.

Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.

Transcriptional analysis of the multiple Sry genes and developmental program at the onset of testis differentiation in the rat.

BACKGROUND: The commonly used laboratory rat, Rattus norvegicus, is unique in having multiple Sry gene copies found on the Y chromosome, with different copies encoding amino acid variations that influence the resulting protein function. It is not clear which Sry genes are expressed at the onset of testis differentiation or how their expression correlates with that of other genes in testis-determination pathways. METHODS: Here, two independent E11-E14 developmental RNAseq datasets show that multiple Sry genes are expressed at E12-E13. RESULTS: The identified copies expressed during testis initiation include Sry4A, Sry1, and Sry3C, which are conserved in every strain of Rattus norvegicus with genomes sequenced to date. CONCLUSIONS: This work represents a first step in defining the complex environment of rat testis differentiation that can open the door for generating sex reversal model systems using embryo manipulation techniques that have been available in the mouse but not the rat.

Super-capacity information-carrying systems encoded with spontaneous Raman scattering.

Optical multiplex barcode systems have been significantly boosting the throughput of scientific discovery. A high volume of barcodes can be made from combinations of distinct spectral bands and intensity levels. However, the practical capacity often reaches a ceiling due to the overlaps of signal frequencies or intensities when massive information is written on individual carriers. In this paper, we built super-capacity information-carrying systems by tuning vibrational signals into octal numeral intensities in multiple bands of Raman-silent regions. This novel approach experimentally yielded the largest capacity of distinct optical barcodes to date. The experiments of encoding ASCII and Unicode systems to write and read languages indicate that the Raman coding method provides a new strategy for super-capacity data storage. In addition, multiplex screening of a cell-binding ligand was implemented to demonstrate the feasibility of this technology for fast and in situ high-throughput bio-discovery. These information-carrying systems may open new scenarios for the development of high-throughput screening, diagnostics and data storage.

XX sex chromosome complement promotes atherosclerosis in mice.

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.

Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting specific mRNA species for degradation or interfering with translation. Specific miRNAs are key regulators of adipogenesis, and are expressed at different levels in adipose tissue from lean and obese mice. The degree of lipid accumulation and distribution of white adipose tissue differs between males and females, and it is unknown whether sex differences in adipose tissue-specific miRNA expression may contribute to this dimorphism. Typically, sex differences are attributed to hormones secreted from ovaries or testes. However, the sex chromosome complement (XX versus XY) is also a determinant of sex differences and may regulate miRNA expression in adipocytes. RESULTS: To identify sex differences in adipose tissue miRNA expression and to understand the underlying mechanisms, we performed high-throughput miRNA sequencing in gonadal fat depots of the Four Core Genotypes mouse model. This model, which consists of XX female, XX male, XY female, and XY male mice, allowed us to assess independent effects of gonadal type (male vs. female) and sex chromosome complement (XX vs. XY) on miRNA expression profiles. We have also assessed the effects of a high fat diet on sex differences in adipose tissue miRNA profiles. We identified a male-female effect on the overall miRNA expression profile in mice fed a chow diet, with a bias toward higher expression in male compared to female gonadal adipose tissue. This sex bias disappeared after gonadectomy, suggesting that circulating levels of gonadal secretions modulate the miRNA expression profile. After 16 weeks of high fat diet, the miRNA expression distribution was shifted toward higher expression in XY vs. XX adipose tissue. Principal component analysis revealed that high fat diet has a substantial effect on miRNA profile variance, while gonadal secretions and sex chromosome complement each have milder effects. CONCLUSIONS: Our results demonstrate that the overall miRNA expression profile in adipose tissue is influenced by gonadal hormones and the sex chromosome complement, and that expression profiles change in response to gonadectomy and high fat diet. Differential miRNA expression profiles may contribute to sex differences in adipose tissue gene expression, adipose tissue development, and diet-induced obesity.

The importance of having two X chromosomes.

Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may explain some features of X chromosome aneuploidies such as in Turner and Klinefelter syndromes.

Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes.

We measured diurnal rhythms of food intake, as well as body weight and composition, while varying three major classes of sex-biasing factors: activational and organizational effects of gonadal hormones, and sex chromosome complement (SCC). Four Core Genotypes (FCG) mice, comprising XX and XY gonadal males and XX and XY gonadal females, were either gonad-intact or gonadectomized (GDX) as adults (2.5months); food intake was measured second-by-second for 7days starting 5weeks later, and body weight and composition were measured for 22weeks thereafter. Gonadal males weighed more than females. GDX increased body weight/fat of gonadal females, but increased body fat and reduced body weight of males. After GDX, XX mice had greater body weight and more fat than XY mice. In gonad-intact mice, males had greater total food intake and more meals than females during the dark phase, but females had more food intake and meals and larger meals than males during the light phase. GDX reduced overall food intake irrespective of gonad type or SCC, and eliminated differences in feeding between groups with different gonads. Diurnal phase of feeding was influenced by all three sex-biasing variables. Gonad-intact females had earlier onset and acrophase (peak) of feeding relative to males. GDX caused a phase-advance of feeding, especially in XX mice, leading to an earlier onset of feeding in GDX XX vs. XY mice, but earlier acrophase in GDX males relative to females. Gonadal hormones and SCC interact in the control of diurnal rhythms of food intake.

Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes.

OBJECTIVE: The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. APPROACH AND RESULTS: We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male-female gonadal sex and XX-XY chromosome complement. Gonadectomy of adult mice revealed that the male-female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male-female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. CONCLUSIONS: We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels.

The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two.

AIM: Sex differences in coronary heart disease have been attributed to sex hormones, whereas the potential role of the sex chromosomes has been ignored so far. Here, we investigated the role of the sex chromosomes in causing sex differences in myocardial ischaemia/reperfusion (I/R) injury. METHODS AND RESULTS: We used two unique mouse models, the 'four core genotypes' [XX mice with ovaries (XXF) or testes (XXM) and XY mice with ovaries (XYF) or testes (XYM)] and XY* (gonadal male or female mice with one or two X chromosomes). All mice were gonadectomized (GDX). In vivo or isolated Langendorff-perfused hearts were subjected to I/R injury. The in vivo infarct size in XY mice was significantly smaller than XX mice regardless of their gonadal type (24.5 ± 4.1% in XYF and 21.8 ± 3.3% in XYM vs. 37.0 ± 3.2% in XXF and 35.5 ± 2.1% in XXM, P < 0.01). Consistent with the results in vivo, the infarct size was markedly smaller and cardiac functional recovery was significantly better in XY mice compared with XX ex vivo. The mitochondrial calcium retention capacity was significantly higher in XY compared with XX mice (nmol/mg protein: XXF = 126 ± 9 and XXM = 192 ± 45 vs. XYF = 250 ± 56 and XYM = 286 ± 51, P < 0.05). In XY* mice, mice with 2X chromosomes had larger infarct size (2X females = 41.4 ± 8.9% and 2X males = 46.3 ± 9.5% vs. 1X females = 23.7 ± 3.9% and 1X males = 26.6 ± 6.9%, P < 0.05) and lower heart functional recovery, compared with those with 1X chromosome. Several X genes that escape X inactivation (Eif2s3x, Kdm6a, and Kdm5c) showed higher expression in XX than in XY hearts. CONCLUSION: XX mice have higher vulnerability to I/R injury compared with XY mice, which is due to the number of X chromosomes rather than the absence of the Y chromosome.